Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihyper cholesterolemic agents that functions by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein: R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
.sup.+ is PA1 .sup.+ is ##STR3## wherein N is ##STR4## R.sup.5 is H or OH; M is ##STR5## PA1 N is ##STR6## and when d is a double bond, M is ##STR7## PA1 R.sup.2 and R.sup.3 are independently selected from: PA1 R.sub.4 is selected from: PA1 R.sub.13 is selected from: PA1 X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or a group selected from: PA1 A is O or S(O)n; PA1 R.sub.1 is selected from: PA1 R.sup.2 and R.sup.3 are independently selected from PA1 R.sub.1 is selected from: PA1 R.sub.2 and R.sub.3 are independently selected from: PA1 A is O; a is a single bond; and PA1 R.sub.1 is 2-methyl-2-butyl or 2-butyl; and R.sub.2 and R.sub.3 are independently selected from: H, CH.sub.3, phenylthiomethyl and hydroxymethyl. PA1 A is S(O).sub.n ; a is a single bond; PA1 R.sub.1 is 2-methyl-2-butyl or 2-butyl; and PA1 R.sub.2 and R.sub.3 are independently selected from: PA1 H, CH.sub.3 and hydroxymethyl. PA1 A is N-R.sup.13 ; PA1 R.sub.1 is selected from: PA1 R.sup.2 and R.sup.3 are independently selected from PA1 R.sub.1 is selected from:
R.sup.6 is hydroqen or hydroxy; R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond,
U.S. patent application Ser. No. 048,136 filed May 15, 1987 discloses 6-substituted compounds of the above general formula wherein R.sup.- is ##STR8## wherein R is ##STR9## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. patent application Ser. No. 142,361 filed Jan. 7, 1988 discloses lovastatin analogs wherein the 6-position is gem-disubstituted: ##STR10## R.sup.2 and R.sup.3 are alkyl or substituted alkyl moieties.